MOLECULAR MECHANISMS OF DYSTROPHIC CARDIOMYOPATHY Abstract Cardiovascular diseases continue to be a leading cause of death and disability in USA. Duchenne Muscular Dystrophy (DMD) is a genetic disorder caused by mutations in the dystrophin gene that affects the structure and function of both cardiac and skeletal muscles. Heart failure has become a leading cause of fatalities in DMD patients. Our goal is to understand the molecular mechanisms underlying dystrophic cardiomyopathy, and to develop novel therapeutic strategies to treat this disease. We have first discovered CIP as a novel cardiomyocyte-enriched protein and we showed CIP is dynamically regulated in hypertrophic and dilated hearts. CIP physically interacts with dystrophin, mutation of which causes DMD. Importantly, we observed that CIP overexpression protects DMD mice (Mdx) from cardiomyopathy. These exciting findings have identified CIP as a novel component of the dystrophic cardiomyopathy pathway. In this study, we will define the molecular nature of CIP action and test the therapeutic potential of this protein in protecting the heart from developing dystrophic cardiomyopathy. More specifically, we will: 1) define the functional mechanism of CIP in dystrophic cardiomyopathy and heart failure; 2) test the therapeutic potential of CIP in dystrophic cardiomyopathy; 3) test the hypothesis that CIP mediates the oxidative stress signaling pathway in dystrophic cardiomyopathy. Studies proposed in this application will yield new insights into the pathogenesis of cardiomyopathy in DMD. Furthermore, we will demonstrate that therapy is a viable strategy to treat dystrophic cardiomyopathy in both murine and human disease models.